An oral cephem agent, cefditoren pivoxil of the formula (5), is in wide used as an antibacterial agent having a broad antimicrobial spectrum and strong antibacterial activities.

With cephalosporin antibiotics having alkenyl at the 3-position, the steric structure of the alkenyl group at the 3-position has Z configuration as is the case with cefditoren pivoxil. The mechanism of producing outstanding antibacterial activities on gram-negative bacteria is attributable partly to this feature. For the antibacterial pharmaceutical agent to exhibit its effect, therefore, it is important to diminish to the greatest possible extent the presence of the geometrical E-isomer of cefditoren pivoxil. In preparing cefditoren pivoxil, attempts have been made to improve the Z-isomer content of process intermediates.
For example, a process has been disclosed for preparing an amine salt or hydrochloric acid salt of a Z/E mixture of 7-amino-3-[2-(4-methylthiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid, which is a process intermediate, to deplete the amine salt or hydrochloric acid salt of 7-amino-3-[(E)-2-(4-methylthiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid by adsorption chromatography with an ion exchange resin or active carbon (see, for example, Patent Literature 1)                [Patent Literature 1] JP1995-188250 A        
With the process disclosed in the literature, however, Examples 4 and 5 result in E-isomer contents of 14% and 2%, respectively, which are not satisfactory.
In recent years, chromatography is used for separation and purification as industrial means especially in the pharmaceutical industry, but the recovery of the eluent or the regeneration of the adsorbent filling the column heavily burdens the industry, so that the procedure used can not always be an optimum method. Improvements in the purity of pharmaceuticals to be produced and several percent increases in the amount of production are distinctly reflected on the efficacy of the drug and production cost. Thus, high purities and high yields are required of manufacturing processes.
An object of the present invention is to provide an economically outstanding process for preparing 7-amino-3-[(Z)-2-(4-methylthiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid and salts thereof with a minimized E-isomer content.